Association of Metabolic Dysregulation With Volumetric Brain Magnetic Resonance Imaging and Cognitive Markers of Subclinical Brain Aging in Middle-Aged Adults: The Framingham Offspring Study

Veterans Administration Boston HealthcareSystem, Boston, MA, USA.
Diabetes care (Impact Factor: 8.42). 06/2011; 34(8):1766-70. DOI: 10.2337/dc11-0308
Source: PubMed


Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer's disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults.
Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998-2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C).
We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007).
Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.

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Available from: Sudha Seshadri, Jun 17, 2015
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    • "Numerous prospective studies have reported that the prevalence of cognitive decline and neurodegeneration increases in patients with type 2 diabetes mellitus (T2DM) and in those with metabolic syndrome (MetS) (Roriz-Filho et al., 2009; Singh-Manoux et al., 2012; Yates, Calder, & Ed Rainger, 2014). Although the association between impaired cognition and mental disorders such as late-life depression has been attributed to the physical ageing of individuals, chronic abnormal physical status such as overweight, obesity, and MetS may also play a critical role in the progression of cognitive impairment and neurodegeneration (Farooqui, Farooqui, Panza, & Frisardi, 2012; Luppino et al., 2010; Singh-Manoux et al., 2012; Tan et al., 2011; Yates, Sweat, Yau, Turchiano, & Convit, 2012). Obesity accompanied by hyperglycaemia, hyperlipidaemia, and hypertension is closely associated with cognitive impairment in early old age (Singh-Manoux et al., 2012), likely because poor dietary patterns induce hyperglycaemia and insulin resistance , causing elevated advanced glycation end-products (AGEs), receptors for AGEs (RAGEs) (Li et al., 2013), and cerebral vascular dysfunction (Kamal, Biessels, Duis, & Gispen, 2000; Wang, Ross-Cisneros, Aggarwal, Liang, & Sadun, 2009). "

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    • "Besides being major risk factors for heart disease, stroke, and early mortality (Alexander et al. 2003; Chobanian et al. 2003), each of these risk factors is associated with decline in cognitive abilities late in life, including clinical dementia syndromes (Debette et al. 2011; Joas et al. 2012; Kivipelto et al. 2001; Stewart et al. 2009; Whitmer, Sidney, Selby, Johnston, and Yaffe 2005). Vascular risk factors are believed to increase risk of cognitive decline by promoting progressive, clinically silent brain injury over the course of years or even decades (Debette et al. 2011; Knopman et al. 2011; Korf et al. 2004; Maillard et al. 2012; Tan et al. 2011). Such brain injury, manifested through lesions, tissue loss, and neural dysfunction on brain MRI, is among the most consistently replicated risk factors for late-life cognitive decline to date (Bombois et al. 2008; Carlson et al. 2008; Kuller et al. 2003; Lopez et al. 2003; O&apos;Sullivan et al. 2004). "
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    ABSTRACT: For some researchers, the relationship between prevalent cardiovascular risk factors and late-life cognitive decline is not worthy of further study. It is already known that effective treatment of vascular risk factors lowers risk of such major outcomes as stroke and heart attack, the argument goes; thus, any new information about the relationship between vascular risk factors and another major outcome - late-life cognitive decline-- is unlikely to have an impact on clinical practice. The purpose of this review is to probe the logic of this argument by focusing on what is known, and what is not known, about the relationship between vascular risk factors and late-life cognitive decline. The unknowns are substantial: in particular, there is relatively little evidence that current vascular risk factor treatment protocols are adequate to prevent late-life cognitive decline or the clinically silent brain injury that precedes it. In addition, there is relatively little understanding of which factors lead to differential vulnerability or resilience to the effects of vascular risk factors on silent brain injury. Differential effects of different classes of treatments are similarly unclear. Finally, there is limited understanding of the impact of clinically-silent neurodegenerative disease processes on cerebrovascular processes. Further study of the relationships among vascular risk factors, brain injury, and late-life cognitive decline could have a major impact on development of new vascular therapies and on clinical management of vascular risk factors, and there are promising avenues for future research in this direction.
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    • "Notably, along with the T2DM population, the prediabetic population also tends to exhibit cognitive dysfunction [48] and reduction in total brain volume [49]. As conditions like hyperinsulinemia and impaired glucose tolerance start to emerge during the prediabetic stage, cognitive dysfunction as well as brain alterations may occur even in the early stages of T2DM. "
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